APPLICANT'S ABSTRACT: The aim of the study is to determine the efficacy of oral nalmefene in reducing drinking and smoking in patients with concurrent nicotine and alcohol dependence. Opiate antagonists have demonstrated efficacy in reducing alcohol craving and consumption in alcoholics. Laboratory studies suggest opiate antagonist administration reduces symptoms of nicotine dependence. Nalmefene, an experimental opiate antagonist, was associated with reductions in both smoking and drinking in a 12-week double-blind pilot study of 23 patients with concurrent nicotine and alcohol dependence, with no increase in body weight or depressive symptoms. We propose to randomly assign 166 patients with DSM IV Nicotine and Alcohol Dependence to a double-blind, placebo-controlled 12-week trial of either a fixed daily dose of 80 mg nalmefene or placebo. All subjects will receive weekly individual coping skills and NCI smoking cessation behavioral therapy in keeping with good clinical practice and in recognition of the psychosocial aspects of these disorders. Drinking and smoking data will be collected from multiple sources including self-report diaries and time line interviews, collateral informant interviews, expired air carbon monoxide and breath alcohol levels, plasma nicotine/cotinine assays, liver function tests, and urine toxicology screens. Medication compliance will be assessed with MEMS computerized medication bottle caps that record date and time of each use. Posttreatment follow-up interviews will be conducted at 3 and 6 months to determine smoking and drinking status and persistence of any treatment effects.